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Physiological Functions and Pathological Effects of Microglia

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 20 September 2025 | Viewed by 3367

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Prof. Dr. Hiroshi Nakanishi

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Guest Editor

Department of Pharmacology, Faculty of Pharmacy, Yasuda Women’s University, Yasuhigashi, Hiroshima 731-0153, Japan
Interests: microglia; brain inflammation; cathepsins; Alzheimer’s disease; Porphyromonas gingivalis

Special Issue Information

Dear Colleagues,

Microglia comprise a variety of subsets with multiple roles in the healthy and diseased brain. Microglia engulf dendritic spines and prune connections between neurons to establish mature patterns of connection during postnatal development. On the other hand, a fault in synaptic elimination and disturbance of the microglial circadian clock system are accepted characteristic abnormalities in neuropsychiatric disorders, including autism. Furthermore, excessive inflammatory and immune responses mediated by pathological microglia are involved in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease. Therefore, in this Special Issue, we aim to retrieve the bank of data on physiological functions and pathological effects of microglia, which may aid in gaining a better understanding of their emergent properties in the brain.

Prof. Dr. Hiroshi Nakanishi
Guest Editor

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Keywords

circadian clock
homeostasis
immune response
microglia
neurodegenerative diseases
neuroinflammation
neuropsychiatric disorders
neuromodulation
phagocytosis
synaptic pruning

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Published Papers (4 papers)

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Research

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23 pages, 5387 KiB

Open AccessArticle

Tabernanthalog, a Non-Hallucinogenic Psychedelic, Alleviates Cancer-Induced Cognitive Deficits via Serotonergic Pathways

by Masahide Arinaga, Jun Yamada, Shoichiro Maeda, Ayumi Okamura, Yuto Oshima, Liye Zhang, Yiying Han, Kyoko M. Iinuma and Shozo Jinno

Int. J. Mol. Sci. 2025, 26(15), 7519; https://doi.org/10.3390/ijms26157519 (registering DOI) - 4 Aug 2025

Abstract

Cancer-related cognitive impairment (CRCI)—encompassing anxiety, depression, and memory deficits—significantly diminishes the quality of life in patients with cancer, yet remains underrecognized in clinical practice. In this study, we investigated the therapeutic potential of tabernanthalog (TBG), a non-hallucinogenic analog of psychedelic compounds, as a novel intervention for CRCI using a Lewis lung carcinoma (3LL) mouse model. Behavioral assessments revealed heightened anxiety-like behavior and memory impairment following 3LL cell transplantation. Biochemical analysis revealed reduced tryptophan levels in both blood and hippocampal tissue, accompanied by the downregulation of serotonergic receptor genes and upregulation of pro-inflammatory cytokine genes in the hippocampus of tumor-bearing mice. Additionally, microglial density and morphological activation were markedly elevated. TBG treatment reversed these behavioral deficits, improving both anxiety-related behavior and memory performance. These effects were associated with the normalization of microglial density and morphology, as well as the restoration of serotonergic receptor and cytokine gene expression. In vitro, TBG partially suppressed neuroinflammatory gene expression in BV-2 microglial cells exposed to conditioned medium from 3LL cells. Collectively, these findings suggest that TBG alleviates CRCI-like symptoms by modulating neuroinflammation and microglial activation. This study highlights TBG as a promising therapeutic candidate for improving cognitive and emotional functioning in patients with cancer. Full article

(This article belongs to the Special Issue Physiological Functions and Pathological Effects of Microglia)

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21 pages, 3299 KiB

Open AccessArticle

Cognitive and Affective Dysregulation in Neuropathic Pain: Associated Hippocampal Remodeling and Microglial Activation

by Anna Tyrtyshnaia, Igor Manzhulo, Anastasia Egoraeva and Darya Ivashkevich

Int. J. Mol. Sci. 2025, 26(13), 6460; https://doi.org/10.3390/ijms26136460 - 4 Jul 2025

Viewed by 490

Abstract

Neuropathic pain is a persistent and exhausting condition which results from damage to the nervous system and is often accompanied by emotional and cognitive impairments. In this study, we investigated dynamic changes in pain-related behaviors over 8 weeks using a spared nerve injury (SNI) model in male C57Bl/6 mice. We examined behavioral outcomes in conjunction with glial activation, neurogenesis, and glutamatergic signaling in the hippocampus to elucidate the mechanisms underlying cognitive and affective alterations associated with chronic pain. Our findings demonstrate that SNI-induced neuropathic pain progressively increases anxiety-like behavior and impairs both working and long-term memory. These behavioral deficits are accompanied by significant activation of microglia and astrocytes, a reduction in hippocampal neurogenesis, and a decrease in the expression of NMDA and AMPA glutamate receptor subunits and the scaffolding protein PSD-95. Taken together, our results suggest that hippocampal neuroinflammation and associated synaptic dysfunction contribute to the affective and cognitive disturbances observed in chronic pain, providing insight into potential molecular targets for therapeutic intervention. Full article

(This article belongs to the Special Issue Physiological Functions and Pathological Effects of Microglia)

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17 pages, 3942 KiB

Open AccessArticle

Noradrenaline Synergistically Enhances Porphyromonas gingivalis LPS and OMV-Induced Interleukin-1β Production in BV-2 Microglia Through Differential Mechanisms

by Sakura Muramoto, Sachi Shimizu, Sumika Shirakawa, Honoka Ikeda, Sayaka Miyamoto, Misato Jo, Uzuki Takemori, Chiharu Morimoto, Zhou Wu, Hidetoshi Tozaki-Saitoh, Kosuke Oda, Erika Inoue, Saori Nonaka and Hiroshi Nakanishi

Int. J. Mol. Sci. 2025, 26(6), 2660; https://doi.org/10.3390/ijms26062660 - 15 Mar 2025

Cited by 3 | Viewed by 1145

Abstract

Infection with Porphyromonas gingivalis (Pg), which is a major periodontal pathogen, causes a large number of systemic diseases based on chronic inflammation such as diabetes and Alzheimer’s disease (AD). However, it is not yet fully understood how Pg can augment local systemic immune and inflammatory responses during progression of AD. There is a strong association between depression and elevated levels of inflammation. Noradrenaline (NA) is a key neurotransmitter that modulates microglial activation during stress conditions. In this study, we have thus investigated the regulatory mechanisms of NA on the production of interleukin-1β (IL-1β) by microglia following stimulation with Pg virulence factors, lipopolysaccharide (LPS), and outer membrane vesicles (OMVs). NA (30–1000 nM) significantly enhanced the mRNA level, promoter activity, and protein level of IL-1β up to 20-fold in BV-2 microglia following treatment with Pg LPS (10 μg/mL) and OMVs (150 μg of protein/mL) in a dose-dependent manner. Pharmacological studies have suggested that NA synergistically augments the responses induced by Pg LPS and OMVs through different mechanisms. AP-1 is activated by the β₂ adrenergic receptor (Aβ₂R)-mediated pathway. NF-κB, which is activated by the Pg LPS/toll-like receptor 2-mediated pathway, is required for the synergistic effect of NA on the Pg LPS-induced IL-1β production by BV-2 microglia. Co-immunoprecipitation combined with Western blotting and the structural models generated by AlphaFold2 suggested that cross-coupling of NF-κB p65 and AP-1 c-Fos transcription factors enhances the binding of NF-κB p65 to the IκB site, resulting in the synergistic augmentation of the IL-1β promoter activity. In contrast, OMVs were phagocytosed by BV-2 microglia and then activated the TLR9/p52/RelB-mediated pathway. The Aβ₂R/Epac-mediated pathway, which promotes phagosome maturation, may be responsible for the synergistic effect of NA on the OMV-induced production of IL-1β in BV-2 microglia. Our study provides the first evidence that NA synergistically enhances the production of IL-1β in response to Pg LPS and OMVs through distinct mechanisms. Full article

(This article belongs to the Special Issue Physiological Functions and Pathological Effects of Microglia)

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Review

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21 pages, 1045 KiB

Open AccessReview

Microglia/Macrophages in Autoimmune Demyelinating Encephalomyelitis (Multiple Sclerosis/Neuromyelitis Optica)

by Ryo Yamasaki

Int. J. Mol. Sci. 2025, 26(8), 3585; https://doi.org/10.3390/ijms26083585 - 10 Apr 2025

Cited by 1 | Viewed by 1137

Abstract

Microglia and macrophages are critical mediators of immune responses in the central nervous system. Their roles range from homeostatic maintenance to the pathogenesis of autoimmune demyelinating diseases such as multiple sclerosis and neuromyelitis optica spectrum disorder. This review explores the origins of microglia and macrophages, as well as their mechanisms of activation, interactions with other neural cells, and contributions to disease progression and repair processes. It also highlights the translational relevance of insights gained from animal models and the therapeutic potential of targeting microglial and macrophage activity in multiple sclerosis and neuromyelitis optica spectrum disorder. Full article

(This article belongs to the Special Issue Physiological Functions and Pathological Effects of Microglia)

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